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Current management of chronic kidney disease (CKD) in type 1 diabetes centres on glycaemic control, renin-angiotensin system inhibition and optimisation of risk factors including blood pressure, lipids and body weight. While these therapeutic approaches have significantly improved outcomes among people with type 1 diabetes and CKD, this population remains at substantial elevated risk for adverse kidney and cardiovascular events, with limited improvements over the last few decades. The significant burden of CKD and CVD in type 1 diabetes populations highlights the need to identify novel therapies with the potential for heart and kidney protection. Over the last decade, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide 1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists have emerged as potent kidney-protective and/or cardioprotective agents in type 2 diabetes. The consistent, substantial kidney and cardiovascular benefits of these agents has led to their incorporation into professional guidelines as foundational care for type 2 diabetes. Furthermore, introduction of these agents into clinical practice has been accompanied by a shift in the focus of diabetes care from a 'glucose-centric' to a 'cardiorenal risk-centric' approach. In this review, we evaluate the potential translation of novel type 2 diabetes therapeutics to individuals with type 1 diabetes with the lens of preventing the development and progression of CKD.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , GlucosaRESUMEN
AIM/HYPOTHESIS: The risk of progressing from autoantibody positivity to type 1 diabetes is inversely related to age. Separately, whether age influences patterns of C-peptide loss or changes in insulin sensitivity in autoantibody-positive individuals who progress to stage 3 type 1 diabetes is unclear. METHODS: Beta cell function and insulin sensitivity were determined by modelling of OGTTs performed in 658 autoantibody-positive participants followed longitudinally in the Diabetes Prevention Trial-Type 1 (DPT-1). In this secondary analysis of DPT-1 data, time trajectories of beta cell function and insulin sensitivity were analysed in participants who progressed to type 1 diabetes (progressors) to address the impact of age on patterns of metabolic progression to diabetes. RESULTS: Among the entire DPT-1 cohort, the highest discriminant age for type 1 diabetes risk was 14 years, with participants aged <14 years being twice as likely to progress to type 1 diabetes as those aged ≥14 years. At study entry, beta cell glucose sensitivity was impaired to a similar extent in progressors aged <14 years and progressors aged ≥14 years. From study entry to stage 3 type 1 diabetes onset, beta cell glucose sensitivity and insulin sensitivity declined in both progressor groups. However, there were no significant differences in the yearly rate of decline in either glucose sensitivity (-13.7 [21.2] vs -11.9 [21.5] pmol min-1 m-2 [mmol/l]-1, median [IQR], p=0.52) or insulin sensitivity (-22 [37] vs -14 [40] ml min-1 m-2, median [IQR], p=0.07) between progressors aged <14 years and progressors aged ≥14 years. CONCLUSIONS/INTERPRETATION: Our data indicate that during progression to stage 3 type 1 diabetes, rates of change in declining glucose and insulin sensitivity are not significantly different between progressors aged <14 years and progressors aged ≥14 years. These data suggest there is a predictable course of declining metabolic function during the progression to type 1 diabetes that is not influenced by age.
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Diabetes Mellitus Tipo 1 , Resistencia a la Insulina , Humanos , Autoanticuerpos , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Glucosa , Prueba de Tolerancia a la Glucosa , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Complejo CD3/antagonistas & inhibidores , Diabetes Mellitus Tipo 1/prevención & control , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Niño , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Progresión de la Enfermedad , Método Doble Ciego , Exantema/inducido químicamente , Femenino , Prueba de Tolerancia a la Glucosa , Antígeno HLA-DR3 , Antígeno HLA-DR4 , Humanos , Recuento de Linfocitos , Linfopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Linfocitos T/inmunología , Adulto JovenRESUMEN
The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a writing group to develop a consensus statement on the management of type 1 diabetes in adults. The writing group has considered the rapid development of new treatments and technologies and addressed the following topics: diagnosis, aims of management, schedule of care, diabetes self-management education and support, glucose monitoring, insulin therapy, hypoglycaemia, behavioural considerations, psychosocial care, diabetic ketoacidosis, pancreas and islet transplantation, adjunctive therapies, special populations, inpatient management and future perspectives. Although we discuss the schedule for follow-up examinations and testing, we have not included the evaluation and treatment of the chronic microvascular and macrovascular complications of diabetes as these are well-reviewed and discussed elsewhere. The writing group was aware of both national and international guidance on type 1 diabetes and did not seek to replicate this but rather aimed to highlight the major areas that healthcare professionals should consider when managing adults with type 1 diabetes. Though evidence-based where possible, the recommendations in the report represent the consensus opinion of the authors. Graphical abstract.
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Diabetes Mellitus Tipo 1 , Adulto , Glucemia , Automonitorización de la Glucosa Sanguínea , Consenso , Diabetes Mellitus Tipo 1/terapia , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéuticoRESUMEN
Over the last few years, technological advances have led to tremendous improvement in the management of type 1 diabetes (T1D). Artificial pancreas systems have been shown to improve glucose control compared with conventional insulin pump therapy. However, clinically significant hypoglycemic and hyperglycemic episodes still occur with the artificial pancreas. Postprandial glucose excursions and exercise-induced hypoglycemia represent major hurdles in improving glucose control and glucose variability in many patients with T1D. In this regard, dual-hormone artificial pancreas systems delivering other hormones in addition to insulin (glucagon or amylin) may better reproduce the physiology of the endocrine pancreas and have been suggested as an alternative tool to overcome these limitations in clinical practice. In addition, novel ultra-rapid-acting insulin analogs with a more physiological time-action profile are currently under investigation for use in artificial pancreas devices, aiming to address the unmet need for further improvements in postprandial glucose control. This review article aims to discuss the current progress and future outlook in the development of novel ultra-rapid insulin analogs and dual-hormone closed-loop systems, which offer the next steps to fully closing the loop in the artificial pancreas.
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Complicaciones de la Diabetes/prevención & control , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Páncreas Artificial , Glucemia/análisis , Glucagón/administración & dosificación , Humanos , Insulina/administración & dosificación , Sistemas de Infusión de Insulina , Polipéptido Amiloide de los Islotes Pancreáticos/administración & dosificaciónRESUMEN
AIM: To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE-3 by modelling and simulation analyses. MATERIALS AND METHODS: Independent of data from EASE-3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient-level, exposure-response modelling in the EASE-2 clinical study. A primary semi-mechanistic model evaluated efficacy considering clinical insulin dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, insulin dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE-3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE-3 but not EASE-2) included a lower 2.5 mg dose. A placebo-corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher doses (10 mg and 25 mg). Since only one trial included the lower dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg dose by modelling and simulation analyses. RESULTS: The simulated 26-week mean HbA1c change was -0.41% without insulin dose adjustment and -0.29% at 26 weeks with insulin dose adjustment. A simplified (descriptive) model excluding insulin dose and mean daily glucose confirmed the -0.29% HbA1c change that would have been observed had the EASE-2 population received a 2.5 mg dose for 26/52 weeks. CONCLUSIONS: The HbA1c benefit of low-dose empagliflozin directly observed in the EASE-3 trial was confirmed by two modelling and simulation approaches.
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Diabetes Mellitus Tipo 1 , Insulina , Compuestos de Bencidrilo/efectos adversos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Glucósidos , Hemoglobina Glucada , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéuticoRESUMEN
Much progress has been made in type 1 diabetes research. Biological replacement of islet function has been achieved with pancreas transplantation and with islet transplantation. In the future, human embryonic stem cells and/or induced pluripotent stem cells may offer a potentially unlimited source of cells for islet replacement. Another potential strategy is to induce robust beta cell replication so that regeneration of islets can be achieved. Immune interventions are being studied with the hope of arresting the type 1 diabetes disease process to either prevent the disease or help preserve beta cell function. Mechanical replacement of islet cell function involves the use of glucose sensor-controlled insulin infusion systems. As all of these avenues are pursued, headlines often overstate the case, thus hyping any given advance, which provides enormous hope for patients and families seeking a cure for type 1 diabetes. Often, however, it is an animal study or a pilot trial that is being described. The reality is that translation to successful trials in human beings may not be readily achievable. This article discusses both the hype and the hopes in type 1 diabetes research.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/cirugía , Animales , Humanos , Sistemas de Infusión de Insulina , Trasplante de Islotes Pancreáticos , Trasplante de Células MadreRESUMEN
AIMS/HYPOTHESIS: We aimed to examine: (1) whether specific glucose-response curve shapes during OGTTs are predictive of type 1 diabetes development; and (2) the extent to which the glucose-response curve is influenced by insulin secretion. METHODS: Autoantibody-positive relatives of people with type 1 diabetes whose baseline OGTT met the definition of a monophasic or biphasic glucose-response curve were followed for the development of type 1 diabetes (n = 2627). A monophasic curve was defined as an increase in OGTT glucose between 30 and 90 min followed by a decline of ≥ 0.25 mmol/l between 90 and 120 min. A biphasic response curve was defined as a decrease in glucose after an initial increase, followed by a second increase of ≥ 0.25 mmol/l. Associations of type 1 diabetes risk with glucose curve shapes were examined using cumulative incidence curve comparisons and proportional hazards regression. C-peptide responses were compared with and without adjustments for potential confounders. RESULTS: The majority of participants had a monophasic curve at baseline (n = 1732 [66%] vs n = 895 [34%]). The biphasic group had a lower cumulative incidence of type 1 diabetes (p < 0.001), which persisted after adjustments for age, sex, BMI z score and number of autoantibodies (p < 0.001). Among the monophasic group, the risk of type 1 diabetes was greater for those with a glucose peak at 90 min than for those with a peak at 30 min; the difference persisted after adjustments (p < 0.001). Compared with the biphasic group, the monophasic group had a lower early C-peptide (30-0 min) response, a lower C-peptide index (30-0 min C-peptide/30-0 min glucose), as well as a greater 2 h C-peptide level (p < 0.001 for all). CONCLUSIONS/INTERPRETATION: Those with biphasic glucose curves have a lower risk of progression to type 1 diabetes than those with monophasic curves, and the risk among the monophasic group is increased when the glucose peak occurs at 90 min than at 30 min. Differences in glucose curve shapes between the monophasic and biphasic groups appear to be related to C-peptide responses.
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Péptido C/metabolismo , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/metabolismo , Prueba de Tolerancia a la Glucosa/métodos , Adulto , Glucemia/metabolismo , Femenino , Humanos , Insulina/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND/OBJECTIVE: The extent of influence of BMI and age on C-peptide at the diagnosis of type 1 diabetes (T1D) is unknown. We thus studied the impact of body mass index Z-scores (BMIZ) and age on C-peptide measures at and soon after the diagnosis of T1D. METHODS: Data from Diabetes Prevention Trial-Type 1 (DPT-1) participants <18.0 years at diagnosis was analyzed. Analyses examined associations of C-peptide measures with BMIZ and age in 2 cohorts: oral glucose tolerance tests (OGTTs) at diagnosis (n = 99) and mixed meal tolerance tests (MMTTs) <6 months after diagnosis (n = 80). Multivariable linear regression was utilized. RESULTS: Fasting and area under the curve (AUC) C-peptide from OGTTs (n = 99) at diagnosis and MMTTs (n = 80) after diagnosis were positively associated with BMIZ and age (P < .001 for all). Associations persisted when BMIZ and age were included as independent variables in regression models (P < .001 for all). BMIZ and age explained 31%-47% of the variance of C-peptide measures. In an example, 2 individuals with identical AUC C-peptide values had an approximate 5-fold difference in values after adjustments for BMIZ and age. The association between fasting glucose and C-peptide decreased markedly when fasting C-peptide values were adjusted (r = 0.30, P < .01 to r = 0.07, n.s.). CONCLUSIONS: C-peptide measures are strongly and independently related to BMIZ and age at and soon after the diagnosis of T1D. Adjustments for BMIZ and age cause substantial changes in C-peptide values, and impact the association between glycemia and C-peptide. Such adjustments can improve assessments of ß-cell impairment at diagnosis.
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Péptido C/sangre , Diabetes Mellitus Tipo 1/sangre , Adolescente , Factores de Edad , Índice de Masa Corporal , Niño , Diabetes Mellitus Tipo 1/diagnóstico , Femenino , Humanos , MasculinoRESUMEN
Importance: Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect. Objective: To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes. Design, Setting, and Participants: Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016. Interventions: Randomization to receive 7.5 mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186). Main Outcome and Measures: The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported. Results: Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7-12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5-4.6 years) in the main study group, diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes was not significantly different between the 2 groups (hazard ratio [HR], 0.87; 95% CI, 0-1.2; P = .21). In secondary stratum 1 (n = 55), diabetes was diagnosed in 13 participants (48.1%) in the oral insulin group and in 19 participants (70.3%) in the placebo group. The time to diabetes was significantly longer with oral insulin (HR, 0.45; 95% CI, 0-0.82; P = .006). The HR for time to diabetes for the between-group comparisons for the 116 participants in the other secondary stratum was 1.03 (95% CI, 0-2.11; P = .53) and for the entire cohort of 560 participants was 0.83 (95% CI, 0-1.07; P = .11), which were not significantly different. The most common adverse event was infection (n = 254), with 134 events in the oral insulin group and 120 events in the placebo group, but no significant study-related adverse events occurred. Conclusions and Relevance: Among autoantibody-positive relatives of patients with type 1 diabetes, oral insulin at a dose of 7.5 mg/d, compared with placebo, did not delay or prevent the development of type 1 diabetes over 2.7 years. These findings do not support oral insulin as used in this study for diabetes prevention. Trial Registration: clinicaltrials.gov Identifier: NCT00419562.
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Diabetes Mellitus Tipo 1/prevención & control , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Administración Oral , Adolescente , Autoanticuerpos/sangre , Niño , Preescolar , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/genética , Familia , Femenino , Estudios de Seguimiento , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Insulina/inmunología , Masculino , Insuficiencia del TratamientoRESUMEN
This report details the development, validation, and utility of the Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score (DPTRS) for type 1 diabetes (T1D). Proportional hazards regression was used to develop the DPTRS model which includes the glucose and C-peptide sums from oral glucose tolerance tests at 30, 60, 90, and 120 min, the log fasting C-peptide, age, and the log BMI. The DPTRS was externally validated in the TrialNet Natural History Study cohort (TNNHS). In a study of the application of the DPTRS, the findings showed that it could be used to identify normoglycemic individuals who were at a similar risk for T1D as those with dysglycemia. The DPTRS could also be used to identify lower risk dysglycemic individuals. Risk estimates of individuals deemed to be at higher risk according to DPTRS values did not differ significantly between the DPT-1 and the TNNHS; whereas, the risk estimates for those with dysglycemia were significantly higher in DPT-1. Individuals with very high DPTRS values were found to be at such marked risk for T1D that they could reasonably be considered to be in a pre-diabetic state. The findings indicate that the DPTRS has utility in T1D prevention trials and for identifying pre-diabetic individuals.
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Diabetes Mellitus Tipo 1/diagnóstico , Autoanticuerpos/sangre , Glucemia/análisis , Péptido C/sangre , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Estado Prediabético , Factores de RiesgoRESUMEN
OBJECTIVE: Type 1 diabetes (T1D) results from the inflammatory destruction of pancreatic ß-cells. In this study, we investigated the effect of docosahexaenoic acid (DHA) supplementation on stimulated inflammatory cytokine production in white blood cells (WBC) from infants with a high genetic risk for T1D. RESEARCH DESIGN AND METHODS: This was a multicenter, two-arm, randomized, double-blind pilot trial of DHA supplementation, beginning either in the last trimester of pregnancy (41 infants) or in the first 5 months after birth (57 infants). Levels of DHA in infant and maternal red blood cell (RBC) membranes and in breast milk were analyzed by gas chromatography/mass spectrometry. Inflammatory cytokines were assayed from whole blood culture supernatants using the Luminex multiplex assay after stimulation with high dose lipopolysaccharide (LPS), 1 µg/mL. RESULTS: The levels of RBC DHA were increased by 61-100% in treated compared to control infants at ages 6-36 months. There were no statistically significant reductions in production of the inflammatory cytokines, IL-1ß, TNFα, or IL-12p40 at any of the six timepoints measured. The inflammatory marker, high-sensitivity C-reactive protein (hsCRP), was significantly lower in breast-fed DHA-treated infants compared to all formula-fed infants at the age of 12 months. Three infants (two received DHA) were removed from the study as a result of developing ≥two persistently positive biochemical islet autoantibodies. CONCLUSIONS: This pilot trial showed that supplementation of infant diets with DHA is safe and fulfilled the pre-study goal of increasing infant RBC DHA levels by at least 20%. Inflammatory cytokine production was not consistently reduced.
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Citocinas/metabolismo , Diabetes Mellitus Tipo 1/prevención & control , Ácidos Docosahexaenoicos/uso terapéutico , Autoanticuerpos/sangre , Proteína C-Reactiva/metabolismo , Diabetes Mellitus Tipo 1/inmunología , Suplementos Dietéticos , Ácidos Docosahexaenoicos/análisis , Ácidos Docosahexaenoicos/metabolismo , Método Doble Ciego , Eritrocitos/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Leucocitos/metabolismo , Masculino , Leche Humana/química , Proyectos Piloto , Embarazo , Vitamina D/sangreRESUMEN
BACKGROUND: Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved ß-cell function in recent-onset type 1 diabetes. METHODS: We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6-45 years and those in the anakinra trial were aged 18-35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. FINDINGS: Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI -0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (-0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. INTERPRETATION: Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. FUNDING: National Institutes of Health and Juvenile Diabetes Research Foundation.
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Anticuerpos Monoclonales/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Factores Inmunológicos/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Adolescente , Adulto , Análisis de Varianza , Anticuerpos Monoclonales Humanizados , Péptido C/efectos de los fármacos , Niño , Método Doble Ciego , Femenino , Humanos , Células Secretoras de Insulina/efectos de los fármacos , Interleucina-1/antagonistas & inhibidores , Masculino , Resultado del Tratamiento , Adulto JovenRESUMEN
Introduction: The rise of digital health applications utilizing continuous glucose monitoring (CGM) allows for novel assessments of glucose management and weight changes in people without diabetes. The Signos System incorporates a digital health app paired with a CGM to provide information and prompts aimed to help people without diabetes to manage weight. Objectives: The primary objective of this study was to determine whether the average timing of the latest chronological glucose excursion ("spike") was correlated with amount of weight loss. Methods: This was a retrospective analysis of prospectively obtained glucose and weight data from people without diabetes who enrolled in the Signos System from November 2021 to August 2023. Participants were provided CGMs as well as encouraged to use the Signos app with personalized advice and logging capabilities for weight, food, physical activity, heart rate, sleep, and activities. "Latest spike time" (LST) was retrospectively derived from CGM data and compared with weight changes at 6 months. Results: Nine hundred and twenty-six subjects met the inclusion criteria including sufficient days wearing a CGM and a weight log within 15 days of 6 months from their first weight log. There was a strong correlation between an earlier spike time and increased weight loss. The top quintile of subjects, with an average LST before 5:41 PM, lost over three times as much weight as the bottom quintile of users, with LST after 8:40 PM; this separation was predictable within 1 month of data. Conclusion: In a large population of obese people without diabetes, continuous glucose data, specifically a novel metric "LST," was highly correlated with percentage of total body weight loss at 6 months. This research suggests that for people attempting weight loss, review and alteration of behaviors relating to later glucose excursions may be of specific benefit.
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BACKGROUND: CD8+ T regulatory (Treg) cells that recognize the nonclassical class 1b molecule Qa-1/human leukocyte antigen E (Q/E CD8+ Treg cells) are important in maintaining self-tolerance. We sought to investigate the role that these T cells play in type 1 diabetes (T1D) pathogenesis and whether an intervention targeting this mechanism may delay T1D progression. METHODS: We conducted a phase 1/2, randomized, double-blind, placebo-controlled trial of the autologous dendritic cell therapy AVT001 that included participants at least 16 years of age, within 1 year of T1D diagnosis, and with ex vivo evidence of a defect in Q/E CD8+ Treg function. Patients were randomly assigned in a 2:1 ratio to AVT001 or placebo, which was administered in three monthly intravenous infusions. The primary end point was safety; efficacy end points included changes from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal, hemoglobin A1c (HbA1c), and insulin dose. RESULTS: Sixteen patients received AVT001, and nine received placebo. Similar rates and severity of adverse events were observed in both groups. None of the patients in the AVT001 group had serious adverse events through visit day 360. Compared with placebo, treatment with ATV001 was associated with less decline from baseline log-transformed C-peptide AUC (nmol/l), with the treatment effect between AVT001 and placebo at day 150 of 0.09 (95% confidence interval [CI], 0.03 to 0.15) and at day 360 of 0.10 (95% CI, 0.04 to 0.15). No clear differences in change in HbA1c and insulin dose from baseline were observed between groups. Estimated treatment effects of AVT001 versus placebo at day 360 were -0.17% (95% CI, -0.60 to 0.26%) for HbA1c and -0.06 U/kg/day (95% CI, -0.14 to 0.02) for daily insulin dose. CONCLUSIONS: In this phase 1/2 trial, AVT001 did not result in dose-limiting adverse events. Potential signals of efficacy observed here warrant further evaluation in a fully powered trial. (Funded by Avotres Inc. and the Division of Diabetes, Endocrinology, and Metabolic Diseases; ClinicalTrials.gov number, NCT03895996.).
Asunto(s)
Células Dendríticas , Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/inmunología , Masculino , Femenino , Células Dendríticas/inmunología , Células Dendríticas/trasplante , Método Doble Ciego , Adulto , Adulto Joven , Persona de Mediana Edad , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Adolescente , Linfocitos T Reguladores/inmunología , Insulina/uso terapéutico , Péptido C/sangre , Péptido C/metabolismoRESUMEN
OBJECTIVE: To explore associations of HLA class II genes (HLAII) with the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Next-generation targeted sequencing was used to genotype eight HLAII genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, DPB1) in 1,216 participants from the Diabetes Prevention Trial-1 and Randomized Diabetes Prevention Trial with Oral Insulin sponsored by TrialNet. By the linkage disequilibrium, DQA1 and DQB1 are haplotyped to form DQ haplotypes; DP and DR haplotypes are similarly constructed. Together with available clinical covariables, we applied the Cox regression model to assess HLAII immunogenic associations with the disease progression. RESULTS: First, the current investigation updated the previously reported genetic associations of DQA1*03:01-DQB1*03:02 (hazard ratio [HR] = 1.25, P = 3.50*10-3) and DQA1*03:03-DQB1*03:01 (HR = 0.56, P = 1.16*10-3), and also uncovered a risk association with DQA1*05:01-DQB1*02:01 (HR = 1.19, P = 0.041). Second, after adjusting for DQ, DPA1*02:01-DPB1*11:01 and DPA1*01:03-DPB1*03:01 were found to have opposite associations with progression (HR = 1.98 and 0.70, P = 0.021 and 6.16*10-3, respectively). Third, DRB1*03:01-DRB3*01:01 and DRB1*03:01-DRB3*02:02, sharing the DRB1*03:01, had opposite associations (HR = 0.73 and 1.44, P = 0.04 and 0.019, respectively), indicating a role of DRB3. Meanwhile, DRB1*12:01-DRB3*02:02 and DRB1*01:03 alone were found to associate with progression (HR = 2.6 and 2.32, P = 0.018 and 0.039, respectively). Fourth, through enumerating all heterodimers, it was found that both DQ and DP could exhibit associations with disease progression. CONCLUSIONS: These results suggest that HLAII polymorphisms influence progression from islet autoimmunity to T1D among at-risk subjects with islet autoantibodies.
Asunto(s)
Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/prevención & control , Seroconversión , Genotipo , Haplotipos , Progresión de la Enfermedad , Cadenas HLA-DRB1/genética , Cadenas beta de HLA-DQ/genética , Alelos , Frecuencia de los GenesRESUMEN
Type 1 diabetes is a chronic autoimmune disease in which destruction of pancreatic ß-cells causes life-threatening metabolic dysregulation. Numerous approaches are envisioned for new therapies, but limitations of current clinical outcome measures are significant disincentives to development efforts. C-peptide, a direct byproduct of proinsulin processing, is a quantitative biomarker of ß-cell function that is not cleared by the liver and can be measured in the peripheral blood. Studies of quantitative measures of ß-cell function have established a predictive relationship between stimulated C-peptide as a measure of ß-cell function and clinical benefits. C-peptide levels at diagnosis are often high enough to afford glycemic control benefits associated with protection from end-organ complications of diabetes, and even lower levels offer protection from severe hypoglycemia in type 1 diabetes, as observed in large prospective cohort studies and interventional trials of islet transplantation. These observations support consideration of C-peptide not just as a biomarker of ß-cell function but also as a specific, sensitive, feasible, and clinically meaningful outcome defining ß-cell preservation or restoration for clinical trials of disease-modifying therapies. Regulatory acceptance of C-peptide as a validated surrogate for demonstration of efficacy would greatly facilitate development of disease-modifying therapies for type 1 diabetes.